title: Aluminum(III) interferes with the structure and the activity of the peptidyl-prolyl cis-trans isomerase (Pin1): a new mechanism contributing to the pathogenesis of Alzheimer's disease and cancers?
abstract: The enzyme peptidyl-prolyl cis-trans isomerase (Pin1) may play an important role in preventing the development of Alzheimer's disease (AD). The structural and functional stability of Pin1 is extremely important. Previously, we have determined the stability of Pin1 under stressed conditions, such as thermal treatment and acidic-pH. Considering that aluminum (Al(III)) is well known for its potential neurotoxicity in the pathogenesis of AD, we examined whether Al(III) affects the structure and function of Pin1, by means of a PPIase activity assay, intrinsic fluorescence, circular dichroism (CD) spectroscopy, FTIR, and differential scanning calorimetry (DSC). The intrinsic tryptophan fluorescence measurements mainly show that Al(III) may bind to the clusters nearby W11 and W34 in the WW domain of Pin1, quenching the intrinsic fluorescence of the two tryptophan residues, which possibly results in the decreased binding affinity of Pin1 to substrates. The secondary structural analysis as revealed by FTIR and CD measurements indicate that Al(III) induces the increase in β-sheet and the decrease in α-helix in Pin1. Furthermore, the changes of the thermodynamic parameters for Pin1 as monitored by DSC confirm that the thermal stability of Pin1 significantly increases in the presence of Al(III). The Al(III)-induced structural changes of Pin1 result in a sharp decrease of the PPIase activity of Pin1. To some extent, our research is suggestive that Al(III) may inhibit the isomerization activity of Pin1 in vivo, which may contribute to the pathogenesis of AD.
authors.affiliation: Key Laboratory of Bio-resources and Eco-environment of the Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, PR China.
authors.forename: Jing-Zhang
authors.initials: JZ
authors.lastname: Wang
authors.forename: Ji
authors.initials: J
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Lin
authors.forename: Yong-Guang
authors.initials: YG
authors.lastname: Han
authors.forename: Yue
authors.initials: Y
authors.lastname: Luo
authors.forename: Lei
authors.initials: L
authors.lastname: Xi
authors.forename: Lin-Fang
authors.initials: LF
authors.lastname: Du
mesh_terms: D000077410:Aluminum Chloride; D017607:Aluminum Compounds / Q000737:chemistry*; D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology; D002152:Calorimetry, Differential Scanning; D002712:Chlorides / Q000737:chemistry*; D002942:Circular Dichroism; D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D019696:Peptidylprolyl Isomerase / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D012996:Solutions; D017550:Spectroscopy, Fourier Transform Infrared; D013816:Thermodynamics; D014364:Tryptophan / Q000737:chemistry
chemical_list: D017607:Aluminum Compounds; D002712:Chlorides; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D011994:Recombinant Proteins; D012996:Solutions; D000077410:Aluminum Chloride; D014364:Tryptophan; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase
keywords: Aluminum; Alzheimer's disease; Pin1; Spectral methodologies; Stability